Pyridines 2-halo-: 2-alkylation

Imidazo[4,5-6]pyridine, 1,2-dimethyl-methylation, 5, 618 Imidazo[4,5-6]pyridine, 2,3-diphenyl-synthesis, 5, 636 Imidazo[4,5-6]pyridine, 6-halo-alkylation, 5, 616 aminomethylation, 5, 616 Imidazo[4,5-6]pyridine, 2-(4-hydroxy-6-methylpyrimidin-2-ylamino)-synthesis, 5, 637... 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

If the heterocyclic base contains several pyridine-type nitrogens select can also be observed. Indeno[l,2-b]quinoxalines, for example, are quaternized at the N-10 atom.110 The alkylation of heterocycles conta one pyrrole-type nitrogen and several pyridine-type nitrogens is appar selective (e.g., indolo[2,3-b]quinoxaline).201 The yields of quaternary however, are extremely low,201 even if phenacyl halides or a-halo ester used.207 Perhaps the resultant quaternary salts are dealkylated.200,207... 

Biphenyldicarboxylicacids.1 Phenanthrenequinone (1) isoxidized by oxygen in the presence of CuCl in pyridine to 2,2 -biphenyldicarboxylic acid (2) in high yield. Under the same conditions the monoimine 3, prepared in situ, is oxidized to 4. Amino and hydroxyl substituents interfere with this reaction, but alkyl, nitro, and halo groups are well-tolerated. 

Thus, the reaction of both aryl (Table 9, entries 1-3) and alkyl diazo ketones (entries 5-7, 9-11) with (HF) /pyridine and a halide source gives a-fluoro-a-halo ketones. The best yields are generally obtained in the case of the fluoroiodo derivatives (entries 3, 7 and 11). Diazo... 

Ben2 yl-type chlorides are converted to the corresponding cyanides much more rapidly (85-90%). Ring substituents include alkyl, halo, carbethoxy and nitro groups. The more reactive benzyl halides, particularly the p-methoxy derivatives, are subject to extensive alcoholysis when ethanol is employed as the solvent. The successful use of acetone, acetonitrile, and phenylacetonitrile as solvents has been described. Conversion by cuprous cyanide and pyridine has been successfully applied to benzyl chloride as well as to di-o-tolylchloro-methane. It is interesting to find that treatment of a-chloroethylbenzene, C,H,CH(C1)CH, with cuprous cyanide gives 1,3-diphenyI-l-butene,... 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

Disconnection of the ethers 113a is guided by our mechanistic knowledge that nucleophilic substitution is possible on alkyl halides, and on 2-halo-pyridines such as 114, but not easy on halobenzenes. 

Syntheses of tndoliztnes carrying substituents in the pyridine ring are not numerous but substituted a-picolines quatemized (review [1870]) with an a-halo ketone (review [B S]) are convenient substrates for cyclization to indolizines or related compounds the reaction is mediated by ammonia on its own at 5°C or with hydrogencarbonate, TEA or methanolic sodium hydroxide. 2-Alkylpyri-dines may be A -alkylated and cyclized in a one-pot reaction (see Chapter 104, Section I.l). 

Nan-Homg (Stan) Lin and his associates next embarked on exploration of analogues of 11 that incorporate substituents on the pyridine ring.16 The starting plan was to examine representative halo and alkyl substituents at each open position. Several of the requisite 3-hy-droxypyridines (i.e. 2-methyl, 6-methyl, 2-bromo, 5-chloro) were commercially available, and several other target modifications were accessible using the chemistry shown in Figure 6. Thus, syntheses of... 

The pyrimidine bases cytosine, uracil, and thymine cannot be directly alkylated by halo sugars. The nucleophilicity of the pyridone-type ring nitrogens is much reduced relative to the pyridine-type nitrogens present in the purine bases. The dialkoxypyrimidines are reactive, and dealkylation occurs at the alkylated nitrogen. This is known as the Hilbert-Johnson procedure A recent modification employs... 

Although many phenylacetamides were successfully alkylated with 2-bromo-pyridine, the corresponding thioamides were not. The pyrrolidone XI-14was employed as the active methylene compound in a condensation with 2-bromopyridines. ° Treatment of quaternary salts of halo- or alkoxy-pyridines... 

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